The present invention refers to a stereoselective process for the preparation of 6xcex1-fluorosteroids of formula (I) reported hereinafter, useful in the preparation of anti-inflammatory pharmaceutical formulations.
The availability of a process for the preparation of pregnane fluoro derivatives, which might predominantly yield 6xcex2-fluoro substituted isomers, well known anti-inflammatory agents, is very important from a pharmacological point of view, since the corresponding 6xcex2-fluoro derivatives do not exert any pharmacological action.
Many procedures for the preparation of 6-fluoro pregnane derivatives have been developed so far; however, all of them yield mixtures of the two isomers in relatively high 6xcex2/6xcex1 ratios. It follows that the conversion of isomer 6xcex2 into isomer 6xcex1 or repeated purifications are required to obtain the pharmacologically active isomer only.
By way of example, U.S. Pat. No. 2,961,441 discloses the preparation of 6xcex2-fluoro-3-keto-xcex944-pregnenes by fluorination of the corresponding 3-enol esters with perchloryl fluoride, in an inert organic solvent and in the presence of a catalyst. In particular, said patent describes the fluorination on 3,17xcex1,21-triacetoxy derivative. The process yields 6xcex2-fluoro substituted compounds, which are converted into the corresponding 6xcex1 isomers by methods known in the art.
U.S. Pat. No. 3,980,778 describes the preparation of the 6xcex1,9xcex1-difluoro pregnane derivative of formula 
by fluorination, with perchloryl fluoride, of 3,17xcex1,21-trihydroxy-16xcex2-methylpregna-3,5,9-(11)-trien-20-one 3,17,21-triacetate, obtained by causing to react the corresponding 17xcex1,21-dihydroxy-16xcex2-methylpregna-4,9(11)-diene-3,20-dione 21 acetate with isopropenyl acetate.
Said process yields a 6xcex2/6xcex1 isomeric mixture in which isomer 6xcex2 predominates. It follows that, with a view to obtaining a pharmaceutically useful final product, the 6xcex2-fluorosteroid is to be converted into the corresponding 6xcex1-fluoro compound.
In all aforementioned cases, the formation of 3-enol ester, necessary for the steroid activation at the 6-position, brings about the simultaneous acetylation of the hydroxy groups, if any, at 17xcex1- and 21-positions.
Said processes suffer from a number of disadvantages; for example they are not stereoselective and require the use of perchloryl fluoride as a fluorinating agent, an esplosive and highly corrosive reagent that must be handled with special care and must be used with very long reaction times.
The use of other fluorinating agents, such as for example Selectfluor(copyright), Accufluor(copyright) NFSi or Accufluor(copyright) NFTh, on the described substrates yields mixtures with still more unfavourable 6xcex1:6xcex2 ratios.
Therefore, the need for a process for the preparation of 6xcex1-fluorosteroids, free from the disadvantages of the processes known in the art, is deeply felt.
It has surprisingly been found that a high stereoselectivity of the fluorination at the 6-position can be obtained by operating on substrates obtained in order that the 17xcex1-hydroxy group remains unreacted, and by using specific fluorinating agents. It is, therefore, an object of the present invention to provide a process for the preparation of 6xcex1-fluorosteroids of formula (I) 
wherein R is a substituent at the xcex1- or xcex2-position, chosen from H, OH and an alkyl group with from 1 to 4 carbon atoms, Rxe2x80x2 is a carboxyalkyl group with from 1 to 4 carbon atoms in the alkyl chain and wherein a double bond may be present between positions 1 and 2, said process comprising the reaction of the compound of formula (III) with an electrophilic fluorinating agent to give the compound of formula (I) 
wherein R and Rxe2x80x2 are as defined above, and wherein said electrophilic fluorinating agent is selected from the group consisting of N-fluoro N-chloromethyl triethylenediamine bis-tetrafluoroborate, 1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane-bis-tetrafluoroborate, and 1-fluoro-benzenesulfonamide.
The characteristics and advantages of the process of the present invention will be apparent from the detailed description reported herein.